Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacteroides fragilis, which is part of the normal intestinal flora, is a frequent cause of serious disease, especially in diabetic and surgical patients. In these conditions, B. fragilis lipopolysaccharide (LPS) is likely to play a major pathophysiologic role. B. fragilis LPS is structurally different from classical enterobacterial LPS, whose biological activities are mediated by Toll-like receptor 4 (TLR4) activation. The ability of B. fragilis LPS to activate TLR4 and TLR2 was investigated here, since evidence on this issue is scarce and controversial. Each of four different protein-free B. fragilis LPS preparations could induce interleukin-8 responses in cells cotransfected with TLR4/CD14/MD2 but not TLR4/CD14 alone. Two of the preparations also induced cytokine production in cells cotransfected with TLR2/CD14 or in peritoneal macrophages from TLR4 mutant C3H/HeJ mice. Both of these activities, however, were lost after repurification with a modified phenol reextraction procedure. Importantly, all preparations could induce endotoxic shock in TLR2-deficient mice, but not in TLR4 mutant C3H/HeJ mice. Consistent with these findings, anti-TLR4 and anti-CD14, but not anti-TLR2, antibodies could inhibit B. fragilis LPS-induced cytokine production in human monocytes. Collectively, these results indicate that B. fragilis LPS signals via a TLR4/CD14/MD2-dependent pathway, and it is unable to activate TLR2. Moreover, our data document the occurrence of TLR2-activating contaminants even in highly purified B. fragilis LPS preparations. This may explain earlier contradictory findings on the ability of B. fragilis LPS to activate cells in the absence of functional TLR4. These data may be useful to devise strategies to prevent the pathophysiologic changes observed during B. fragilis sepsis and to better understand structure-activity relationships of LPS.
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PMID:Bacteroides fragilis-derived lipopolysaccharide produces cell activation and lethal toxicity via toll-like receptor 4. 1611 79

Septic shock is initiated by a systemic inflammatory response to microbial infection that frequently leads to impaired perfusion and multiple organ failure. Because of its high risk of death, septic shock is a major problem particularly for patients in the intensive care unit. In general, bacterial lipopolysaccharide (LPS) is a strong activator of various immune responses and stimulates monocytes/macrophages to release a variety of inflammatory cytokines. However, overproduction of inflammatory factors in response to bacterial infections is known to cause septic shock, similar to that induced by LPS. Studies of LPS-signaling pathways and downstream inflammatory cytokines may have critical implications in the treatment of sepsis. In recent years, there has been significant progress in understanding the signaling pathways activated by LPS and its receptor Toll-like receptor 4 (TLR4), as well as by tumor necrosis factor alpha (TNFalpha), a potent inflammatory cytokine induced by LPS stimulation. This review briefly summarizes our current knowledge of these signaling pathways and critical signal transducers. Characterization of key signal transducers may allow us to identify tractable, novel targets for the therapeutic interventions of sepsis.
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PMID:Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock. 1613 57

Lipopolysaccharide (LPS) is thought to be an important molecule in myocardial depression in sepsis. Toll-like receptor 4 (TLR4), the lipopolysaccharide receptor, is known to underlie these responses. Because TLR4 is expressed on both cardiac myocytes and immune cells, it is unclear as to which cell type is responsible for myocyte depression. In this article, we present evidence that the early response is likely related to TLR4 on immune cells and most likely macrophages, whereas the more delayed response may involve various immune cells as well as myocytes.
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PMID:Is there a role for cardiomyocyte toll-like receptor 4 in endotoxemia? 1616 10

The family of Toll-like receptors (TLRs) is involved in the defense of an organism to microbial attack. TLR4-induced signaling is involved in infectious diseases, chronic inflammatory diseases and sepsis; therefore, we aimed at modulating TLR4-signaling via ligand-binding soluble receptors. Because recognition of microbial structures shows some species-specific traits, we specifically selected the mouse model for later in vivo studies. We first prepared the N-terminally Flag-tagged mouse (m) recombinant (r) soluble (s) fusion proteins mrsTLR4-IgGFc (T4Fc) and mrsMD-2 in Drosophila melanogaster Schneider 2 (S2) cells. The function of these molecules was tested by inhibition of synthesis of pro-inflammatory cytokines after stimulation of mouse macrophage RAW 264.7 cells with purified lipopolysaccharide (LPS). T4Fc alone had no inhibitory activity; however, a T4Fc/MD-2 complex blocked LPS activity. By analogy with 'cytokine traps', we then prepared a designer molecule (LPS-Trap) by fusing MD-2 to the C-terminus of soluble TLR4 via a flexible linker. LPS-Trap significantly inhibited TNF production by LPS-stimulated RAW 264.7 cells. Thus, the T4Fc/MD-2 complex as well as the LPS-Trap blocked LPS activity in vitro and might thus represent a new therapeutic option in sepsis by neutralization of TLR4-activating ligands.
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PMID:A designed TLR4/MD-2 complex to capture LPS. 1617 55

Despite recent identification of specific pattern recognition receptors (PRR) for distinct microbial structures, data indicating their relevance in human infectious diseases are limited. We determined the expression levels of the Toll-like receptor (TLR)2 and TLR4 by flow cytometry on granulocytes and monocytes of healthy neonates compared with healthy adults. The basal expression of TLR2 was only slightly lower in neonatal phagocytes, whereas no differences could be detected for TLR4. Analyzing neonates with sepsis, we found an impressive up-regulation of TLR2 on blood phagocytes already at initial presentation of symptoms. Comparison with C-reactive protein, IL-8, and IL-6 suggested that TLR2 expression on monocytes is comparably valuable as an early sepsis marker. TLR2 was differentially regulated during neonatal sepsis, showing a constant up-regulation on monocytes but only a transient increase on granulocytes. Surprisingly, TLR4 showed no remarkable changes. Our results revealed a mild deficiency of TLR2 expression in newborns and demonstrated a differential expression of TLR2 but not TLR4 in the course of neonatal sepsis, which could reflect specific inflammatory responses to distinct pathogens. The definition of TLR expression patterns might open a new field of therapeutic targets for neonatal sepsis.
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PMID:Expression of toll-like receptors in neonatal sepsis. 1618 89

Toll-like receptors (TLRs) play a pivotal role in the induction of innate immunity after the transactivation of proinflammatory cytokine genes. However, the responses of TLRs during severe polymicrobial sepsis have not been thoroughly examined. Although dehydroepiandrosterone (DHEA), a steroid hormone, is reported to have an immunomodulatory effect after sepsis, the mechanism responsible for its salutary is not known. To investigate this, male ICR/Jcl mice (5-8 weeks old) were subjected to sepsis by cecal ligation and puncture (CLP) or sham operation. The mice received vehicle or DHEA (40 mg/kg body weight) subcutaneously immediately after the surgery. Plasma IL-10 levels and splenic macrophage TNF-alpha production, as well as the expression levels of CD14, TLR2, and TLR4 mRNAs on splenic macrophages, were assessed 6 h after the surgery. The results indicate that mice with sepsis show a marked increase in the plasma IL-10 levels and a decrease in TNF-alpha production by splenic macrophages. TLR2 and TLR4 mRNA expression levels after CLP were significantly lower compared with those after the sham operation. TNF-alpha production and TLR2 and TLR4 mRNA expression on splenic macrophages are restored with DHEA administration. Furthermore, administration of DHEA after CLP delayed the mortality of animals. These results indicate that the anti-inflammatory phase of sepsis induces a marked down-regulation of TLR expression on splenic macrophages; however, administration of DHEA resulted in the restoration of TLR2 and TLR4 mRNA expression.
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PMID:Dehydroepiandrosterone modulates toll-like receptor expression on splenic macrophages of mice after severe polymicrobial sepsis. 1620 22

Toll-like receptors (TLRs) play an essential role in the detection of invading pathogens and in the induction of host antimicrobial defenses. TLR4, the major endotoxin receptor, and TLR2, with agonists derived principally from gram-positive organisms, are likely to be important in the pathogenesis of sepsis. Both TLR2 and TLR4 agonists regulate important neutrophil functions, including adhesion, generation of reactive oxygen species, and release of chemokines, and activate major proinflammatory signaling pathways, including the nuclear factor- kappa B pathway. TLR stimulation produces only a modest direct inhibition of neutrophil apoptosis, although this signal is greatly amplified by the presence of monocytes, suggesting that regulation of the life span of neutrophils by TLR agonists may be principally mediated by responses of other endotoxin-responsive cells. We suggest that activation of neutrophils by TLRs is highly regulated, permitting acute neutrophil antimicrobial responses to TLR activation while providing a "brake" on inflammation by requiring the presence of mononuclear cells to significantly extend neutrophil survival.
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PMID:The role of Toll-like receptors in the regulation of neutrophil migration, activation, and apoptosis. 1623 41

Lipopolysaccharide (LPS), the principal component of the outer membrane of Gram-negative bacteria, stimulates various cell types to release numerous proinflammatory mediators such as TNF-alpha, IL-6 and IL-12, which may damage cells and lead to organ injury, even sepsis and septic shock. Toll-like receptor 4 (TLR4) has been identified as the receptor involved in the recognition of LPS, but the role of LPS uptake in activating signal transduction remains controversial. In the present study, TNF-alpha was used as a marker of macrophages/ monocytes activated by LPS, and CQ was used as an inhibitor of endosome mature in order to definitude what stage of the signal transduction elicited by LPS was interrupted. We found that there indeed existed internalization of LPS and internalization partially participated in LPS signaling since CQ inhibited cytokine release, and decreased accumulation of FITC-LPS in hPBMCs. In contrast, anti-hTLR4 antibody could decrease cytokine release, but had no inhibition on accumulation of FITC-LPS. This result revealed that inhibition of cytokine release was related to reduction of FITC-LPS accumulation in the cells. But TLR4 on the cell surface couldn't participate in internalization of LPS. Thus, LPS signaling and internalization couldn't be viewed as mutually independent processes.
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PMID:Lipopolysaccharide could be internalized into human peripheral blood mononuclear cells and elicit TNF-alpha release, but not via the pathway of toll-like receptor 4 on the cell surface. 1628 97

Toll-like receptors (TLRs) are now recognized as the major receptors for microbial pathogens on cells of the innate immune system. Recently, TLRs were also identified in many organs including the kidney. However, the cellular distribution and role of these renal TLRs remain largely unknown. In this paper, we investigated the expression of TLR4 in a cecal ligation and puncture (CLP) model of sepsis in Sprague-Dawley rats utilizing fluorescence microscopy. In sham animals, TLR4 was expressed predominantly in Tamm-Horsfall protein (THP)-positive tubules. In CLP animals, TLR4 expression increased markedly in all tubules (proximal and distal), glomeruli, and the renal vasculature. The staining showed a strong apical distribution in all tubules. A moderately less intense cellular signal colocalized partially with the Golgi apparatus. In addition, kidneys from septic rats showed increased expression of CD14 and THP. They each colocalized strongly with TLR4, albeit in different tubular segments. We also imaged the kidneys of live septic animals with two-photon microscopy after fluorescent lipopolysaccharide (LPS) injection. Within 10 min, LPS was seen at the brush border of some proximal tubules. Within 60 min, LPS was fully cytoplasmic in proximal tubules. Conversely, distal tubules showed no LPS uptake. We conclude that TLR4, CD14, and THP have specific renal cellular and tubular expression patterns that are markedly affected by sepsis. Systemic endotoxin can freely access the tubular and cellular sites where these proteins are present. Therefore, locally expressed TLRs and other interacting proteins could potentially modulate the renal response to systemic sepsis.
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PMID:Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. 1633 27

Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gram-negative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-kappaB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.
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PMID:Lipopolysaccharide signaling in endothelial cells. 1635 66


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